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Mapping Aldehyde Dehydrogenase 1A1 Activity using an [18F]Substrate-Based Approach |
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| Authors: | Dr. Raul Pereira Dr. Thibault Gendron Chandan Sanghera Hannah E. Greenwood Joseph Newcombe Dr. Patrick N. McCormick Dr. Kerstin Sander Prof. Dr. Maya Topf Prof. Dr. Erik Årstad Dr. Timothy H. Witney |
| Affiliation: | 1. Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD UK Current address: Department of Imaging Chemistry & Biology, King's College London, St. Thomas' Hospital, London, SE1 7EH UK;2. Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ UK;3. Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ UK Department of Biological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX UK;4. Department of Biological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX UK;5. Centre for Advanced Biomedical Imaging, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD UK |
| Abstract: | Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes to carboxylic acids. Elevated ALDH expression in human cancers is linked to metastases and poor overall survival. Despite ALDH being a poor prognostic factor, the non-invasive assessment of ALDH activity in vivo has not been possible due to a lack of sensitive and translational imaging agents. Presented in this report are the synthesis and biological evaluation of ALDH1A1-selective chemical probes composed of an aromatic aldehyde derived from N,N-diethylamino benzaldehyde (DEAB) linked to a fluorinated pyridine ring either via an amide or amine linkage. Of the focused library of compounds evaluated, N-ethyl-6-(fluoro)-N-(4-formylbenzyl)nicotinamide 4 b was found to have excellent affinity and isozyme selectivity for ALDH1A1 in vitro. Following 18F-fluorination, [18F] 4 b was taken up by colorectal tumor cells and trapped through the conversion to its 18F-labeled carboxylate product under the action of ALDH. In vivo positron emission tomography revealed high uptake of [18F] 4 b in the lungs and liver, with radioactivity cleared through the urinary tract. Oxidation of [18F] 4 b , however, was observed in vivo, which may limit the tissue penetration of this first-in-class radiotracer. |
| Keywords: | [18F]fluorination aldehyde dehydrogenase cancer radiochemistry radiolabeling |